“Most patients demonstrated a stable sawtooth pattern with an increase in tumor burden while on a sunitinib treatment break and decreased tumor burden while receiving sunitinib”, the investigators report in the Journal of Clinical Oncology.

Seven of the 20 patients in the phase II study testing an intermittent dosing regimen guided by computed tomography imaging achieved “prolonged drug holidays” of between 3.2 and 43.6 months before experiencing a 10% or greater gain in tumour burden, they write.

Five patients had an overall increase in tumour burden over time and were switched to the standard 4 weeks on, 2 weeks off sunitinib schedule. One patient with bulky nodal disease who achieved a 17% decrease during the first four cycles, despite several dose reductions, began treatment 5 weeks into the initial 8-week break after showing clinical and radiographical progression.

At time of analysis, four patients were continuing with intermittent sunitinib, 12 had progressed and two patients had discontinued therapy because of side effects. One patient died from an unrelated brain haemorrhage and another patient withdrew from the trial.

“The [objective response rate] of 46% and [median progression-free survival] of 22.4 months observed in this trial are consistent with published data” and “support the hypothesis that an intermittent schedule does not compromise clinical outcome”, say Moshe Ornstein, from Cleveland Clinic Taussig Cancer Institute in Ohio, USA, and co-authors.

The current study used RECIST criteria to monitor 37 patients with treatment-naïve clear cell mRCC after four cycles of sunitinib 50 mg/day for 4 weeks followed by 2 weeks off treatment. Seventeen patients were excluded from beginning intermittent therapy because of progressive disease, toxicity or consent withdrawal at the end of cycle 4.

Treatment was paused for the remaining 20 patients who achieved a 10% or greater reduction in tumour burden – and a median decrease of 45% – and a restaging scan was performed at week 12.

Treatment continued when the patient experienced a 10% or higher increase in tumour burden. At this point, sunitinib was reinitiated for a further two cycles and tumour burden reassessed; patients who did not achieve a minimum 10% reduction continued with sunitinib cycles while those achieving this threshold of response had a further break from treatment.

In all, the 20 patients had 83 breaks, ranging from one to 11 breaks per patient, and a median of three per patient. The breaks lasted a median of 8.3 weeks and sunitinib retreatment lasted a median of 12.0 weeks. This translated to 1296.6 weeks off treatment, corresponding to 216 separate 6-week cycles and a median of nine cycles saved per patient, the researchers emphasize.

The median change in tumour burden was a gain of 1.6 cm during the treatment break and a decrease of 1.4 cm during retreatment, with a median relative increase during the treatment holiday of 44%.

Over the first four cycles of treatment, around half of the patients had a dose reduction to 37.5 mg/day (46%) or 25.0 mg/day (5%). In addition, 24% had their cycle switched to 2 weeks on, 1 week off with or without a dose reduction; these patients continued to intermittent therapy on this regimen.

The most common adverse events were fatigue (89%), mucositis (86%) and thrombocytopenia (84%), with the most common grade 3 events being hypertension (38%), neutropenia (24%) and fatigue (22%).

“The results of this trial suggested that implementation of this approach in select patients may result in reduced toxicities, improved quality of life, cost savings, and potentially improved clinical outcomes”, summarise Moshe Ornstein et al.

“A phase II/III clinical trial in Europe in which patients are randomly assigned to standard sunitinib dosing versus treatment on an intermittent schedule is ongoing”, they conclude.